Nitric oxide (NO) has been shown to have powerful, broad-spectrum antimicrobial activity as well as benefits in wound healing when properly administered [1-3]. The combination of these two attributes makes development of a non-systemic NO delivery approach valuable for hospital and outpatient applications to prevent infection and accelerate wound healing. Such a product would reduce the rate of serious injury- related infections, and promote faster recovery of injured tissue. A recent estimate of the aggregate global wound treatment market reported a current double-digit growth rate and by 2012 the market will likely be $12.5 billion [4, 5]. The high growth rate is a consequence of an increasing aged population, and diabetes- related wounds. However, deployment of NO-based treatments for cutaneous injuries has not been achieved because practical methods for real-time administration have yet to be invented. This Proposal describes a stable small molecule nitric oxide surrogate for topical application as part of a bandage or salve. Controlled delivery will be designed by modifying the molecular structure of these nitric oxide donor surrogates so that different rates of release are obtained once activated and applied to the wound. Formulation of these molecules into a product is outside the scope of this Proposal, however, it is important to consider aspects of this future work in the design process now. As part of this Proposal, we will: 1) design and synthesize 30 novel nitric oxide releasing molecules, 2) test the nitric oxide release kinetics for each molecule in the presence of initiating agents, such as mammalian sera or enzyme solutions, 3) conduct thermal stability studies for each compound, and 4) design, synthesize, and test an additional 15 molecules to optimize physical and efficacy characteristics based on the structure-activity data that is collected in Aim 2. Success in these Aims will provide the molecular foundation required to create a practical and usable product. SARmont, LLC is a drug discovery and design company led by Dr. John Talley, the lead inventor of Celebrex and 7 other NCE that have made it to the marketplace. SARmont provides medicinal chemistry services to the public but maintains carefully chosen internal projects to make the most of our intellectual and laboratory resources. This proposal strongly compliments our knowledge base and expertise, given Dr. Talley's 20 years working in the pain related space and many years working on NO releasing molecules. Our team's track record of success in driving ideas from inception to the marketplace makes us unique and highly qualified to successfully complete the goals of this project. PUBLIC HEALTH RELEVANCE: Nitric oxide (NO) is an important signaling molecule shown to have anti-microbial and wound healing capabilities. Successful deployment of a practical and versatile method for administering NO can have immediate application for civilian and military purposes. Such a product would reduce the rate of serious injury-related infections, and promote faster recovery of injured tissue.